Submissions for variant NM_001048174.2(MUTYH):c.1463C>T (p.Pro488Leu)

gnomAD frequency: 0.00004  dbSNP: rs587778542

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131522	SCV000186516	likely benign	Hereditary cancer-predisposing syndrome	2019-05-02	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Eurofins Ntd Llc (ga)	RCV000656914	SCV000226446	uncertain significance	not provided	2015-04-09	criteria provided, single submitter	clinical testing
GeneDx	RCV000656914	SCV000292632	uncertain significance	not provided	2017-04-25	criteria provided, single submitter	clinical testing	This variant is denoted MUTYH c.1547C>T at the cDNA level, p.Pro516Leu (P516L) at the protein level, and results in the change of a Proline to a Leucine (CCG>CTG). This variant, previously reported as MYH 1505C>T (P502L) using an alternate reference sequence, has been observed in at least one individual with colon adenomas as well as in two healthy controls (Fleischmann 2004, Al-Tassan 2004, Morak 2010). In functional studies, this variant showed complementation of functional deficiency, DNA binding, and glycosylase activity similar to wild-type, but reduced binding to protein partner PCNA (Brinkmeyer 2015, Komine 2015). MUTYH Pro516Leu was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Proline and Leucine differ in some properties, this is considered a semi-conservative amino acid substitution. MUTYH Pro516Leu occurs at a position that is not conserved and is not located in a known functional domain. In silico analyses are inconsistent regarding the effect this variant may have on protein structure or function. Based on currently available information, it is unclear whether MUTYH Pro516Leu is pathogenic or benign. We consider it to be a variant of uncertain significance. Of note, MUTYH-Associated Polyposis (MAP) is a recessive condition associated with two pathogenic variants on opposite chromosomes in MUTYH.
Invitae	RCV000457983	SCV000545757	uncertain significance	Familial adenomatous polyposis 2	2024-01-26	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 516 of the MUTYH protein (p.Pro516Leu). This variant is present in population databases (rs587778542, gnomAD 0.004%). This missense change has been observed in individual(s) with attenuated familial adenomatous polyposis (PMID: 20618354). This variant is also known as p.P502L. ClinVar contains an entry for this variant (Variation ID: 134867). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change does not substantially affect MUTYH function (PMID: 25820570, 26377631). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Mendelics	RCV000457983	SCV000837742	uncertain significance	Familial adenomatous polyposis 2	2018-07-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131522	SCV000903067	benign	Hereditary cancer-predisposing syndrome	2017-03-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000121602	SCV000919787	likely benign	not specified	2021-01-30	criteria provided, single submitter	clinical testing	Variant summary: MUTYH c.1547C>T (p.Pro516Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251856 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1547C>T has been reported in the literature as a monoallelic variant in at-least one individual affected with APC-mutation negative attenuated familial adenomatous polyposis (AFAP stage III) who reported a negative family history (example, Morak_2010). These report(s) do not provide unequivocal conclusions about association of the variant with MUTYH-Associated Polyposis. At least two publications reporting experimental evidence evaluating an impact on protein function were ascertained in the context of this evaluation (example, Brinkemeyer_2015, Komine_2015). Both these studies showed no damaging effect of this variant reporting similar DNA binding and glycosylase activity to wild-type enzyme (Brinkemeyer_2015) and a functionally retained ability to compliment the deficiency in an Mut Y disrupted E Coli system by monitoring spontaneous mutation rates (Komine_2015). However, a reduced affinity for PCNA (proliferation cell nuclear antigen), a binding partner of MUTYH protein, was also reported (Brinkmeyer_2015). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign/benign, n=2; VUS, n=4). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the lack of unequivocal clinical evidence and supportive functional evidence outlined above, the variant was classified as likely benign.
Sema4, Sema4	RCV000131522	SCV002532253	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-20	criteria provided, single submitter	curation
ITMI	RCV000121602	SCV000085799	not provided	not specified	2013-09-19	no assertion provided	reference population